Genome-wide CRISPR screening identifies critical role of phosphatase and tensin homologous (PTEN) in sensitivity of acute myeloid leukemia to chemotherapy  

作　　者：Liming LIN Jingjing TAO Ying MENG Yichao GAN Xin HE Shu LI Jiawei ZHANG Feiqiong GAO Dijia XIN Luyao WANG Yili FAN Boxiao CHEN Zhimin LU Yang XU 

机构地区：[1]Department of Hematology,the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China [2]Zhejiang Provincial Key Laboratory of Pancreatic Disease,the First Affiliated Hospital and Institute of Translational Medicine,Cancer Center,Zhejiang University School of Medicine,Hangzhou 310029,China [3]Institute of Genetics,Zhejiang University,Hangzhou 310058,China [4]Division of Hematopoietic Stem Cell&Leukemia Research,Beckman Research Institute of City of Hope,Duarte,CA 91010,USA [5]Department of Hematology,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

出　　处：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》2024年第8期700-710,共11页浙江大学学报（英文版）B辑（生物医学与生物技术）

基　　金：supported by the Zhejiang Provincial Natural Science Foundation of China(No.LY21H080005);the National Natural Science Foundation of China(Nos.81572920 and 82100171).

摘　　要：Although significant progress has been made in the development of novel targeted drugs for the treatment of acute myeloid leukemia(AML)in recent years,chemotherapy still remains the mainstay of treatment and the overall survival is poor in most patients.Here,we demonstrated the antileukemia activity of a novel small molecular compound NL101,which is formed through the modification on bendamustine with a suberanilohydroxamic acid(SAHA)radical.NL101 suppresses the proliferation of myeloid malignancy cells and primary AML cells.It induces DNA damage and caspase 3-mediated apoptosis.A genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)library screen revealed that phosphatase and tensin homologous(PTEN)gene is critical for the regulation of cell survival upon NL101 treatment.The knockout or inhibition of PTEN significantly reduced NL101-induced apoptosis in AML and myelodysplastic syndrome(MDS)cells,accompanied by the activation of protein kinase B(AKT)signaling pathway.The inhibition of mammalian target of rapamycin(mTOR)by rapamycin enhanced the sensitivity of AML cells to NL101-induced cell death.These findings uncover PTEN protein expression as a major determinant of chemosensitivity to NL101 and provide a novel strategy to treat AML with the combination of NL101 and rapamycin.

关 键 词：Genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)library Phosphatase and tensin homologous(PTEN) Rapamycin Acute myeloid leukemia(AML) CHEMOTHERAPY 

分 类 号：R733.71[医药卫生—肿瘤]